1. Field of Invention
The invention relates to new 2,3-benzodiazepine derivatives substituted by heterocycles, the acid addition salts thereof, as well as the pharmaceutical compositions containing them. The invention also relates to the use of said compounds as AMPA receptor antagonists.
2. Summary of Related Art
Over-activation of glutamate receptors has been associated with several acute and chronic diseases of the central nervous system (“CNS”). Various glutamate receptor antagonists have been investigated as therapeutic modalities (see for example Parsons et al., Drug News Perspect. 11:523 (1998) and Br{hacek over (a)}uner-Osborne et al., J. Med. Chem. 43:2609 (2000)).
AMPA (2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)-propionic acid) type glutamate receptors play a major role in a variety of central nervous system disorders. Inhibition of the activation of AMPA type receptors has been shown to have neuroprotective, antiepileptic and muscle-relaxant effects (see e.g., Cerebrouisc. Brain Metab. Rev 6:225 (1994); Neurology 44 Suppl.8, S14 (1994); J. Pharmacol Exp. Ther. 260:742 (1992)).
Glutamate receptors have been found not only in the CNS but also in peripheral tissues indicating therapeutic potential opportunities beyond the CNS (see e.g., Skerry et al., Trends in Pharm. Sci., Vol. 22, No. 4,174-181 (2001). Respiratory tract inflammation has been postulated to be benefically influenced by NMDA-type glutamate antagonists (Said, Trends in Pharm. Sci. 20:132 (1999); and Said et al., Trends in Pharm. Sci. 22:344 (2001)).
AMPA type receptors can be inhibited by various competitive and non-competitive antagonists. The therapeutic potential of non-competitive an agonists may be superior to that of competitive ones insofar as their activity is not dependent on high concentrations of endogenous glutamate (see e.g., Vizi et al., CNS Drug Rev., 2:91 (1996)). One of the most prominent non-competitive AMPA receptor antagonists is 5-(4-aminophenyl)-8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (also designated as GYKI 52466) possessing remarkable antiepileptic, muscle relaxant and neuroprotective activities. (Tarnawa et al., Eur. J. Pharmacol., 167:193 (1989); Smith, et al., Eur. J. Pharmacol., 187:131 (1990); Ouardouz et al., Neurosci. Lett., 125:5 (1991); Donevan et al., Neuron, 10:51 (993)).
Several non-competitive AMPA antagonists have been described in the literature including 3,4-dihydro-5H- or 4,5-dihydro-3H-2,3-benzodiazepines, containing an acyl group at position 3 of the ring (see e.g., Hungarian Patent Nos. 206,719 B and 219,777 B, U.S. Pat. No. 5,536,832, European Patent Publication No. 0699 677 A1, and British Patent No. 2 311 779, as well as WO 96/04 283, WO 97/28 135, WO 99/07 707, WO 99/07 708 and WO 01/04 122). WO 96/06 606 (corresponding to U.S. Pat. No. 5,795,886) describes several 2,3-benzodiazepine derivatives having aryl and heteroaryl substituents (e.g., pyridyl, thienyl, furyl, phenyl, imidazolyl, benzimidazolyl, etc.) at C3.
The compounds listed above have been found to be particularly useful in diseases in which the over-function of the glutamate system can be detected. Such acute disorders of the CNS include for example stroke, brain ischemia, brain and spinal cord injuries, perinatal hypoxia, hypoglycemic nervous damage, et. Additional chronic illnesses in which selected AMPA antagonists can be applied include e.g., Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, glaucoma, diabetic retinopathy as well as Parkinson's disease. Furthermore, enhanced activity of the glutamate system has also been shown in conditions associated with neural damage (e.g., epilepsy, migraine, urinary bladder incontinence, psychosis—anxiety, schizophrenia etc., drug-abuse, pathological pain, brain edema and tardive dyskinesia) implying an impressive therapeutic potential for AMPA antagonists.
Recently, experimental data suggested that selected AMPA antagonists have beneficial effect on the autoimmune encephalomyelitis elicited in rats, which is the accepted model of multiple sclerosis (Smith et al., Nature Medicine 6:62 (2000)). In addition, AMPA and NMDA receptors in the spinal cord have been implicated in the contraction of the bladder and the urethra, suggesting that AMPA antagonists may be useful in the treatment of urinary incontinence (Nishizawa et al., Adv in Exp. Med. & Biol. Vol. 462, 275 (1999)).
Two 2,3-benzodiazepine derivatives GYKI 52466 (supra), and (R)-7-eacetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (GYKI 53773, also known as Talampanel) were beneficial. The latter has proved to be active in clinical trials on epilepsy patients (Bialer et al., Epilepsy Res. 43:11 (2001)).
In addition, GYKI 52466 has been reported to inhibit growth of selected tumor cell types (colon adenocarcinoma, astrocytoma, breast carcinoma, lung carcinoma and neuroblastoma) (Rzeski et al., Proc. Nat. Acad. Sci. 98:6372 (2001)).